Progressive Renal Remodeling and Glucose Transporter Dysregulation in an Experimental Model of HFpEF associated with Metabolic Syndrome

IntroductionHeart failure with preserved ejection fraction (HFpEF) affects more than half of heart failure patients and is frequently complicated by renal dysfunction, a key factor worsening prognosis. Mechanisms of kidney impairment in HFpEH, however, remain elusive. MethodsObesity-prone (OP) and obesity-resistant (OR) rats were fed respectively with a high-fat diet (HFD) or standard chow for 4 or 12 months (n=10 per group). HFpEF was confirmed in 12-month HFD-fed OP rats using echocardiography and cardiac catheterization, whereas 4-month HFD-fed OP rats did not develop HFpEF. OR rats served as controls. Kidneys were harvested for histological and molecular analyses. ResultsIn HFD-fed OP rats, renal function progressively declined, with significant increases in circulating creatinine and cystatin C. Histological analysis revealed focal segmental hyalinosis in 40% of 4-month OP rats and 100% of HFpEF rats, along with glomerulosclerosis. Tubular atrophy appeared as focal lesions at 4 months and became extensive in HFpEF rats. Immunostaining showed strong apical SGLT2 expression in OR rats, markedly reduced in HFpEF rats, accompanied by increased tubular proliferation (assessed by Ki67 staining) at 4 months, which declined by 12 months, whereas interstitial proliferation predominated in HFpEF rats. Transcriptional analysis revealed early and sustained upregulation of SGLT2 and GLUT2, while GLUT1, SGLT1, GLUT5, G6P transporter, SMVT, SMCT1, and SGLT4 expression remained unchanged or decreased. Fibrosis assessment identified heterogeneous lesions, with α-SMA- negative areas retaining E-cadherin, whereas α-SMA-positive areas showed loss of E-cadherin, suggesting localised epithelial–mesenchymal transition. RNA sequencing confirmed upregulation of pro-fibrotic pathways, altered cell adhesion, and renal transporter dysregulation, reflecting progressive, complex renal injury in HFpEF.Conclusionin our experimental model of HFpEF associated with metabolic syndrome, early renal injury, including tubular remodeling, fibrosis and dysregulation of glucose transporters, precedes cardiac dysfunction, highlighting the kidney as an initial target in disease progression.